The prevalence of type 2 diabetes has increased in both young and old people. We examined age-specific associations and population attributable fractions (PAFs) of risk factors for all-cause and ...cause-specific mortality in people with type 2 diabetes.
We analysed data from 360,202 Chinese with type 2 diabetes who participated in a territory-wide diabetes complication screening programme in Hong Kong between January 2000 and December 2019. We compared the hazard ratios and PAFs of eight risk factors, including three major comorbidities (cardiovascular disease CVD, chronic kidney disease CKD, all-site cancer) and five modifiable risk factors (suboptimal HbA1c, suboptimal blood pressure, suboptimal low-density lipoprotein cholesterol, smoking, and suboptimal weight), for mortality across four age groups (18 to 54, 55 to 64, 65 to 74, and ≥75 years). During a median 6.0 years of follow-up, 44,396 people died, with cancer, CVD, and pneumonia being the leading causes of death. Despite a higher absolute mortality risk in older people (crude all-cause mortality rate: 59.7 versus 596.2 per 10,000 person-years in people aged 18 to 54 years versus those aged ≥75 years), the relative risk of all-cause and cause-specific mortality associated with most risk factors was higher in younger than older people, after mutually adjusting for the eight risk factors and other potential confounders including sex, diabetes duration, lipid profile, and medication use. The eight risk factors explained a larger proportion of mortality events in the youngest (PAF: 51.6%, 95% confidence interval CI 39.1%, 64.0%, p < 0.001) than the oldest (PAF: 35.3%, 95% CI 27.2%, 43.4%, p < 0.001) age group. Suboptimal blood pressure (PAF: 16.9%, 95% CI 14.7%, 19.1%, p < 0.001) was the leading attributable risk factor for all-cause mortality in the youngest age group, while CKD (PAF: 15.2%, 95% CI 14.0%, 16.4%, p < 0.001) and CVD (PAF: 9.2%, 95% CI 8.3%, 10.1%, p < 0.001) were the leading attributable risk factors in the oldest age group. The analysis was restricted to Chinese, which might affect the generalisability to the global population with differences in risk profiles. Furthermore, PAFs were estimated under the assumption of a causal relationship between risk factors and mortality. However, reliable causality was difficult to establish in the observational study.
Major comorbidities and modifiable risk factors were associated with a greater relative risk for mortality in younger than older people with type 2 diabetes and their associations with population mortality burden varied substantially by age. These findings highlight the importance of early control of blood pressure, which could reduce premature mortality in young people with type 2 diabetes and prevent the onset of later CKD and related mortality at older ages.
People with type 2 diabetes (T2D) have increased cancer risk. Liver cancer (LC) has a high prevalence in East Asia and is one of the leading causes of cancer death globally. Diagnosis of LC at early ...stage carries good prognosis. We used stored serum from patients of Hong Kong Diabetes Register before cancer diagnosis to extract RNA to screen for microRNA markers for early detection of LC in T2D. After screening with Affymetrix GeneChip microarray with serum RNA from 19 incident T2D LC (T2D-LC), 20 T2D cancer free (T2D-CF) and 20 non-T2D non-cancer patients, top signals were validated in a 3-group comparison including 1888 T2D-CF, 127 T2D-LC, and 487 T2D patients with non-liver cancer patients using qPCR. We detected 2.55-fold increase in miR-122-5p and 9.21-fold increase in miR-455-3p in the T2D-LC group. Using ROC analysis, miR-122-5p and miR-455-3p jointly predicted LC with an area under the curve of 0.770. After adjustment for confounders, each unit increase of miR-455-3p increased the odds ratio for liver cancer by 1.022. Increased serum levels of miR-122-5p and miR-455-3p were independently associated with increased risk of incident LC in T2D and may serve as potential biomarkers for early detection of LC in T2D.
Type 2 diabetes affects multiple systems. We aimed to compare age- and sex-specific rates of all-cause and cause-specific hospital bed-days between people with and without type 2 diabetes.
Data were ...provided by the Hong Kong Hospital Authority. We included 1,516,508 one-to-one matched people with incident type 2 diabetes (n = 758,254) and those without diabetes during the entire follow-up period (n = 758,254) between 2002 and 2018, followed until 2019. People with type 2 diabetes and controls were matched for age at index date (±2 years), sex, and index year (±2 years). We defined hospital bed-day rate as total inpatient bed-days divided by follow-up time. We constructed negative binominal regression models to estimate hospital bed-day rate ratios (RRs) by age at diabetes diagnosis and sex. All RRs were stratified by sex and adjusted for age and index year. During a median of 7.8 years of follow-up, 60.5% (n = 459,440) of people with type 2 diabetes and 56.5% (n = 428,296) of controls had a hospital admission for any cause, with a hospital bed-day rate of 3,359 bed-days and 2,350 bed-days per 1,000 person-years, respectively. All-cause hospital bed-day rate increased with increasing age in controls, but showed a J-shaped relationship with age in people with type 2 diabetes, with 38.4% of bed-days in those diagnosed <40 years caused by mental health disorders. Type 2 diabetes was associated with increased risks for a wide range of medical conditions, with an RR of 1.75 (95% CI confidence interval 1.73, 1.76; p < 0.001) for all-cause hospital bed-days in men and 1.87 (95% CI 1.85, 1.89; p < 0.001) in women. The RRs were greater in people with diabetes diagnosed at a younger than older age and varied by sex according to medical conditions. Sex differences were most notable for a higher RR for urinary tract infection and peptic ulcer, and a lower RR for chronic kidney disease and pancreatic disease in women than men. The main limitation of the study was that young people without diabetes in the database were unlikely to be representative of those in the Hong Kong general population with potential selection bias due to inclusion of individuals in need of medical care.
In this study, we observed that type 2 diabetes was associated with increased risks of hospital bed-days for a wide range of medical conditions, with an excess burden of mental health disorders in people diagnosed at a young age. Age and sex differences should be considered in planning preventive and therapeutic strategies for type 2 diabetes. Effective control of risk factors with a focus on mental health disorders are urgently needed in young people with type 2 diabetes. Healthcare systems and policymakers should consider allocating adequate resources and developing strategies to meet the mental health needs of young people with type 2 diabetes, including integrating mental health services into diabetes care.
Non-alcoholic fatty liver disease (NAFLD) has become a global epidemic disease. Its incidence is associated with type 2 diabetes mellitus (T2DM). Presently, there is no approved pharmacological ...agents specially developed for NAFLD. One promising disease-modifying strategy is the transplantation of stem cells to promote metabolic regulation and repair of injury.
In this study, a T2DM model was established through 28-week high-fat diet (HFD) feeding resulting in T2DM-associated NAFLD, followed by the injection of bone marrow mesenchymal stem cells (BMSCs). The morphology, function, and transfer of hepatocyte mitochondria were evaluated in both vivo and in vitro.
BMSC implantation resulted in the considerable recovery of increasing weight, HFD-induced steatosis, liver function, and disordered glucose and lipid metabolism. The treatment with BMSC transplantation was accompanied by reduced fat accumulation. Moreover, mitochondrial transfer was observed in both vivo and vitro studies. And the mitochondria-recipient steatotic cells exhibited significantly enhanced OXPHOS activity, ATP production, and mitochondrial membrane potential, and reduced reactive oxygen species levels, which were not achieved by the blocking of mitochondrial transfer.
Mitochondrial transfer from BMSCs is a feasible process to combat NAFLD via rescuing dysfunction mitochondria, and has a promising therapeutic effect on metabolism-related diseases.
Little is known about the lifetime risk of progression to diabetes in the Asian population. We determined remaining lifetime risk of diabetes and life years spent with diabetes in Chinese people with ...normoglycemia and prediabetes. Using territory-wide diabetes surveillance data curated from electronic medical records of Hong Kong Hospital Authority (HA), we conducted a population-based cohort study in 2,608,973 individuals followed from 2001 to 2019. Prediabetes and diabetes were identified based on laboratory measurements, diagnostic codes, and medication records. Remaining lifetime risk and life years spent with diabetes were estimated using Monte Carlo simulations with state transition probabilities based on a Markov chain model. Validations were performed using several sensitivity analyses and modified survival analysis. External replication was performed using the China Health and Retirement Longitudinal Survey (CHARLS) cohort (2010 to 2015). These findings suggest that Hong Kong, an economically developed city in Asia, is confronted with huge challenge of high lifetime risk of diabetes and long life years spent with diabetes, especially in people with prediabetes. Effective public health policies and targeted interventions for preventing progression to diabetes are urgently needed.
Clinical trials have demonstrated that remission of type 2 diabetes can be achieved following sustained weight loss. However, the feasibility of achieving diabetes remission through weight management ...in real-world settings remains unclear. In this study, we aimed to examine the association of weight change at 1 year after diabetes diagnosis with long-term incidence and sustainability of type 2 diabetes remission in real-world settings in Hong Kong.
This was a population-based observational cohort study. The territory-wide Risk Assessment and Management Programme for Diabetes Mellitus (RAMP-DM) provides regular comprehensive assessments of metabolic control and complication screening for people with diabetes in Hong Kong. We included 37,326 people with newly diagnosed type 2 diabetes who were enrolled in the RAMP-DM between 2000 and 2017, followed until 2019. Diabetes remission was defined as 2 consecutive HbA1c <6.5% measurements at least 6 months apart in the absence of glucose-lowering drugs (GLDs) and with no record of GLDs at least 3 months before these measurements. During a median follow-up of 7.9 years, 6.1% (2,279) of people achieved diabetes remission, with an incidence rate of 7.8 (95% CI: 7.5, 8.1) per 1,000 person-years. After adjusting for age at diabetes diagnosis, sex, assessment year, body mass index, other metabolic indices, smoking, alcohol drinking, and medication use, the hazard ratio (HR) for diabetes remission was 3.28 (95% CI: 2.75, 3.92; p < 0.001) for people with ≥10% weight loss within 1 year of diagnosis, 2.29 (95% CI: 2.03, 2.59; p < 0.001) for those with 5% to 9.9% weight loss, and 1.34 (95% CI: 1.22, 1.47; p < 0.001) for those with 0% to 4.9% weight loss compared to people with weight gain. During a median follow-up of 3.1 years, 67.2% (1,531) of people who had achieved diabetes remission returned to hyperglycaemia, with an incidence rate of 184.8 (95% CI: 175.5, 194.0) per 1,000 person-years. The adjusted HR for returning to hyperglycaemia was 0.52 (95% CI: 0.41, 0.65; p < 0.001) for people with ≥10% weight loss, 0.78 (95% CI: 0.68, 0.92; p = 0.002) for those with 5% to 9.9% weight loss, and 0.90 (95% CI: 0.80, 1.01; p = 0.073) for those with 0% to 4.9% weight loss compared to people with weight gain. Diabetes remission was associated with a 31% (HR: 0.69, 95% CI: 0.52, 0.93; p = 0.014) decreased risk of all-cause mortality. The main limitation of the study is that the reliability of HbA1c used to define diabetes remission can be affected by other medical conditions. Furthermore, we did not have data on bariatric surgery.
In this study, greater weight loss within the first year of diabetes diagnosis was associated with an increased likelihood of achieving diabetes remission and a decreased risk of returning to hyperglycaemia among those who had achieved diabetes remission. However, both the incidence of diabetes remission and the probability of its long-term sustainability were low with conventional management in real-world settings, in an era when the importance of weight loss was not fully appreciated. Our study provides evidence for policymakers to design and implement early weight management interventions and diabetes remission initiatives.
Aims/hypothesis
Few large-scale prospective studies have investigated associations between relative leucocyte telomere length (rLTL) and kidney dysfunction in individuals with type 2 diabetes. We ...examined relationships between rLTL and incident end-stage kidney disease (ESKD) and the slope of eGFR decline in Chinese individuals with type 2 diabetes.
Methods
We studied 4085 Chinese individuals with type 2 diabetes observed between 1995 and 2007 in the Hong Kong Diabetes Register with stored baseline DNA and available follow-up data. rLTL was measured using quantitative PCR. ESKD was diagnosed based on the ICD-9 code and eGFR.
Results
In this cohort (mean ± SD age 54.3 ± 12.6 years) followed up for 14.1 ± 5.3 years, 564 individuals developed incident ESKD and had shorter rLTL at baseline (4.2 ± 1.2 vs 4.7 ± 1.2,
p
< 0.001) than the non-progressors (
n
= 3521). On Cox regression analysis, each ∆∆C
t
decrease in rLTL was associated with an increased risk of incident ESKD (HR 1.21 95% CI 1.13, 1.30,
p
< 0.001); the association remained significant after adjusting for baseline age, sex, HbA
1c
, lipids, renal function and other risk factors (HR 1.11 95% CI 1.03, 1.19,
p
= 0.007). Shorter rLTL at baseline was associated with rapid decline in eGFR (>4% per year) during follow-up (unadjusted OR 1.22 95% CI 1.15, 1.30,
p
< 0.001; adjusted OR 1.09 95% CI 1.01, 1.17,
p
= 0.024).
Conclusions/interpretation
rLTL is independently associated with incident ESKD and rapid eGFR loss in individuals with type 2 diabetes. Telomere length may be a useful biomarker for the progression of kidney function and ESKD in type 2 diabetes.
Graphical abstract
Glucokinase activators (GKAs) are an emerging class of glucose lowering drugs that activate the glucose-sensing enzyme glucokinase (GK). Pending formal cardiovascular outcome trials, we applied ...two-sample Mendelian randomisation (MR) to investigate the impact of GK activation on risk of cardiovascular diseases.
We used independent genetic variants in or around the glucokinase gene meanwhile associated with HbA
at genome-wide significance (P < 5 × 10
) in the Meta-Analyses of Glucose and Insulin-related traits Consortium study (N = 146,806; European ancestry) as instrumental variables (IVs) to mimic the effects of GK activation. We assessed the association between genetically proxied GK activation and the risk of coronary artery disease (CAD; 122,733 cases and 424,528 controls), peripheral arterial disease (PAD; 7098 cases and 206,541 controls), stroke (40,585 cases and 406,111 controls) and heart failure (HF; 47,309 cases and 930,014 controls), using genome-wide association study summary statistics of these outcomes in Europeans. We compared the effect estimates of genetically proxied GK activation with estimates of genetically proxied lower HbA
on the same outcomes. We repeated our MR analyses in East Asians as validation.
Genetically proxied GK activation was associated with reduced risk of CAD (OR 0.38 per 1% lower HbA
, 95% CI 0.29-0.51, P = 8.77 × 10
) and HF (OR 0.54 per 1% lower HbA
, 95% CI 0.41-0.73, P = 3.55 × 10
). The genetically proxied protective effects of GKA on CAD and HF exceeded those due to non-targeted HbA
lowering. There was no causal relationship between genetically proxied GK activation and risk of PAD or stroke. The estimates in sensitivity analyses and in East Asians were generally consistent.
GKAs may protect against CAD and HF which needs confirmation by long-term clinical trials.
ABSTRACT
Aims/Introduction
To determine the population health burden attributable to the development of diabetes among women with a history of gestational diabetes mellitus (GDM).
Materials and ...Methods
We conducted a retrospective analysis of women with a history of GDM attending the Hong Kong Hospital Authority between 2000 and 2019. The time‐varying population attributable fraction was calculated.
Results
A total of 76,181 women with a history of gestational diabetes mellitus were included, 6,606 of them developed diabetes during a median follow‐up of 8.6 years. The respective hazard ratios (95% confidence interval) among women with GDM who developed diabetes vs those with GDM only were 2.8 (2.2, 3.7) for cardiovascular disease (CVD), 4.8 (3.0, 7.7) for end‐stage kidney disease (ESKD), 2.2 (1.9, 2.6) for infection‐related hospitalization, and 1.8 (1.3, 2.4) for all‐cause mortality. The development of diabetes was associated with 1.3 (0.8, 1.7), 0.6 (0.3, 0.8), 3.2 (2.4, 4.0), and 0.5 (0.2, 0.9) additional incident cases per 1,000 person‐years, accounting for 24.0% (13.2%, 35.9%), 42.0% (22.5%, 58.8%), 10.8% (7.1%, 14.9%), and 6.0% (−3.1%, 16.1%) of absolute number of CVD, ESKD, infection‐related hospitalization, and all‐cause mortality over 20 years after GDM, respectively.
Conclusions
Diabetes is a significant contributor to the population health burden of some clinical outcomes in women with a history of gestational diabetes mellitus, but other risk factors need to be considered.
In this population‐based cohort of Chinese women with a history of gestational diabetes mellitus, we found that the subsequent development of diabetes in women with GDM increased the hazards of cardiovascular and kidney diseases by 3‐ to 5‐fold, infection‐related hospitalization and all‐cause mortality by 2‐fold, and cancer by 20%. By 20 years post‐GDM, diabetes accounted for close to one half of the new cases of end‐stage kidney disease and one quarter of cardiovascular disease. Our results indicate that diabetes is an important contributor to selected clinical events in women with a history of gestational diabetes mellitus although other risk factors need to be considered.
Cancer is replacing cardiovascular-disease as a leading cause of death in type 2 diabetes (T2D). The association of RAS-inhibitors (RASi) and cancer, including differences between ...angiotensin-converting-enzyme-inhibitor (ACEi) and angiotensin-receptor-blocker (ARBs) as well as their associations independent of blood pressure lowering, remains inconclusive in T2D.
We conducted a cohort study with new-user design in 253,491 patients in the Hong-Kong-Diabetes-Surveillance-Database (HKDSD) in 2002-2019. We evaluated the associations of time-varying RASi use (ACEi and ARBs) with all-site cancer, diabetes-related cancers, and cancer-specific mortality including comparison with new-users of calcium-channel-blockers (CCBs) as an active-comparator group.
Of 253,491, 133,730 (52.8%) were new-RASi and 119,761 (47.2%) were non-RASi users with a median follow-up period of 6.3 (interquartile ragne: 3.4-9.2) years (1,678,719 patient-years). After propensity-score weighting and adjustment for time-varying covariables, RASi use was associated with lower risk of all-site cancer (HR=0.76, 95%CI: 0.74-0.79), diabetes-related cancer (HR=0.79, 95%CI: 0.75-0.84), cancer-specific mortality (HR=0.50, 95%CI: 0.47-0.53), and diabetes-related cancer mortality (HR=0.49, 95%CI: 0.45-0.54) versus non-RASi. Amongst RASi users, ARBs use was associated with lower risk of cancer-specific mortality versus ACEi (HR=0.77, 95%CI: 0.66-0.91). Use of RASi was associated with an estimated-prevention of 2.6 (95%CI: 2.3-3.0) all-site cancer per-1000-person-years and 2.2 (95%CI: 2.0-2.5) cancer-related mortality per-1000-person-years. Lower risk of cancer-specific mortality was similarly observed in new-RASi compared with new-CCBs users.
RASi use was independently associated with lower cancer risk in T2D with stronger associations in users of ARBs than ACEi. The benefits of RASi in patients with diabetes might go beyond cardiovascular-renal protection if confirmed by other real-world studies and trials.
Dr. Aimin Yang was supported by a CUHK Impact-Research-Fellowship Scheme.
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